The principal objective of these studies is to determine host and viral factors that influence genetically-controlled murine resistance to, and recovery from street rabies virus (SRV) infections following viral invasion of the central nervous system. In vitro studies have shown that the cell-to-cell spread of three different rabies viruses in neuronal and non-neuronal cells was inhibited by greater than or equal to 75% with less than one international unit/ml of human antirabies immune globulin. In contrast, only small foci of infection developed in monolayers incubated with antibody. Virus persisted in these few cells for greater than 2 weeks, but spread rapidly to uninfected cells after antibody was removed. Continuing pathogenesis studies have determined that high concentrations of SRV and interferon (INF) were present in the spinal cord (SC) and brains of susceptible A/WySn/J mice, whereas minimal amounts of INF and virus were present in similar tissues of resistant SJL/J mice. Thus, there was a direct correlation between the amount of INF and virus in SC and brains, but no correlation between resistance of SJL/J mice to ascending viral infection in the CNS and the local or systemic expression of INF. Cellular immunity studies have progressed with the establishment of a new and different (SJL/J H-2s) target cell (SSSV) which is easily infected and then lysed with rabies specific antibody and complement. Target cells for use with highly susceptible A/WySn/J(H-2a) and the moderately susceptible C57B1/6/J(H-2b) mice have been identified. The importance of cytotoxic T cells in resistance to SRV are in progress. The importance to T-cells and B-cells in resistance to SRV also are being studied through ablation of the immune response with cyclophosphamide and cyclosporin A (CS-A). Preliminary experiments with CS-A have shown that immunosuppressed SJL/J mice die within four days of virus injection. The importance of T-independent and T-dependent immune responses in resistance to SRV, as identified by the use of these drugs, and the passive transfer of immune cells, serum, and/or monoclonal antibodies is under investigation.